Brain Imaging, Genetics and Treatment for Major Depression

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- Antidepressants help many people with depression, however, some do not seem to benefit as much. Currently, it is not possible to determine who will improve with certain antidepressants. Studies have shown that genes may influence whether an antidepressant works for an individual. Other studies have shown that depressed people tend to have lower levels of a chemical called glutamate in parts of their brain, and that glutamate levels increase after recovering from depression. Researchers want to study the antidepressant citalopram (Celexa) to see how it affects glutamate levels in the brain. They also want to study how a person s genes affect their response to this treatment.

Objectives:

- To see whether glutamate levels and certain genes affect how a person responds to a particular antidepressant medication.

Eligibility:

- Individuals between 25 and 55 years of age who have been diagnosed with major depression (without psychotic features). Participants may not have tried more than three antidepressant treatments.

Design:

Participants will be screened with a physical exam and medical history. They will answer questions about mood and current feelings of depression, as well as family history of depression. Blood and urine samples will be collected.

This study will have two phases. The first phase may last up to 7 weeks depending on current antidepressant use and involves one to seven outpatient visits. The second phase lasts 8 weeks and involves five outpatient visits, one every 2 weeks.

In the first phase, participants will stop taking their current antidepressant medications for at least 2 weeks before the next phase of the study. Participants who are on fluoxetine (Prozac) will need to be off it for 6 weeks.

At the end of this phase, participants will have brain imaging studies to look at brain function and chemistry.

In the second phase, participants will take citalopram at the standard dose. They will answer questions about mood and response to the medication. They will also provide blood and saliva samples for tests.

At the end of this phase, participants will have brain imaging studies to look at brain function and chemistry.

Condition or disease

Intervention/treatment

Phase

Depressive DisorderDepressive Disorder, MajorDepression

Other: Citalopram

Phase 1

Detailed Description:

Objective:

Major depressive disorder (MDD) is a serious, debilitating, life-shortening illness that affects many persons of all ages and backgrounds. Although many patients suffering from MDD can expect improvement with antidepressant treatment, only a minority experience full remission, and little is known about the basis for individual differences in treatment outcome. The rationale for this study follows from the findings that treatment response in major depression is associated with: 1) variation in the genes encoding the serotonin 2A receptor (HTR2A) and the KA1 subunit of the glutamate-kainate receptor (GRIK4); and 2) increases in prefrontal glutamate/glutamine (glx) concentration measured by [+H] magnetic resonance spectroscopy (MRS). The central hypothesis is that genes associated with citalopram treatment outcome modulate glutamate concentrations in prefrontal brain (PFB) and thus facilitate response to citalopram treatment. Such information is important because it would ultimately allow the development of better treatments for MDD.

Study population:

A total of 104 moderate to severe MDD outpatients aged 25-55 with a baseline 17-item Hamilton Depression Rating Scale (HDRS) score of greater than or equal to18 who meet DSM-IV criteria for non-psychotic major depressive disorder (MDD) will be enrolled in the course of the study.

Design:

Subjects will be screened with an on-site research psychiatric evaluation using a structured interview (MINI plus). After screening, participants will provide a DNA sample, which will be analyzed to determine the patient s genotype at several relevant loci. All patients will then complete an eight-week period of citalopram treatment, during which time they will be evaluated bi-weekly with self-report questionnaires and clinician ratings to determine change of MDD symptoms. Participants will also undergo pre- and post-treatment MRS scans to determine glutamate concentration in the prefrontal brain.

Treatment outcome measures:

The Quick Inventory of Depressive Symptomatology - Clinician-Rated (QIDS-C16) will be the primary clinical outcome measure and will be collected at baseline and at each treatment visit. Additionally, levels of glutamate in the prefrontal regions of the brain will be measured by MRS. Clinical response will be defined as a decrease of 50 percent or greater in QIDS-C16 score from baseline, and remission will be defined as a QIDS-C16 score of less than 6.

This proposal is part of a K99 training grant and has undergone extensive external review (K99MH085098-01A2).

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Ages Eligible for Study:

25 Years to 55 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA:

Male and female subjects aged between 25 and 55 years

Score of 18 or higher on the 17-item Hamilton Depression Rating Scale (HDRS17). We have set the HDRS17 cutoff score to greater than or equal to18 to increase the contrast signals between remitters and non-remitters, MRS imaging and genotypic groups.

Meets DSM-IV criteria for chronic or recurrent non-psychotic MDD

No more than 3 failed FDA-approved antidepressant treatments within the current episode

No alcohol use in the last 7 days

Fluent in English or Spanish

Capacity to understand the nature of the study and provide informed consent

EXCLUSION CRITERIA:

Lifetime history of schizophrenia, schizoaffective disorder or psychosis not otherwise specified

Lifetime history of bipolar disorder (I, II, or not otherwise specified)

Lifetime history of anorexia nervosa or bulimia nervosa

Current primary obsessive-compulsive disorder (OCD)

History of intolerability to citalopram

Lack of response to an adequate trial of citalopram or escitalopram in the current or previous episodes of MDD

Have failed to respond to more than three antidepressants during current major depressive episode

Lack of response to 7 or more sessions of ECT in the current or previous episodes of MDD